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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5480_Библиотеки_им_академика_М_И_Перельмана.pdf
Clinical Pharmacokinetics
259
∑ Adverse drug reactions
∑ Emergency procedures
7. Facilities Provided—to include enough required facilities at the ‘testing centre’ as per laid out norms.
8. Analysis Presentation of Data—to give authentic and dependable results
∑ Validation of adopted analytical method
∑ Statistical methods used
∑ Statistical treatment of data analysis of variance (ANOVA)
∑ Format of data
9. Appendix—to provide all other allied information required.
3.4. Bioequivalence Study Design
It is so meticulously designed that it essentially decodes/interprets the observed ‘treatment effects’ that
are invariably produced soon after the administration of dosage forms (or drug products).
In usual practice, the bioequivalence study design is of two types, namely:
∑ Parallel design and
∑ Cross-over design,
which will be discussed briefl y in the following.
3.4.1. Parallel Design
The main objective of the parallel design is to reduce the so-called ‘experimental variables’ to the lowest
ebb so as to completely avoid any possible scope of ‘bias’.
Modus Operandi: In this particular instance, usually two different formulations (or dosage forms) are
duly administered to ‘two groups of volunteers’. In order to avoid a bias, the formulations are adminis-
tered to the respective volunteers randomly.
Merit: The major advantage of the parallel design is that the noticeable inter-volunteer variation
need not be corrected.
Note
Mostly, the inter-volunteer variation is observed to be distinctly more than the actual variation
between two of the dosage forms being studied.
3.4.2. Cross-Over Design
Generally, the cross-over design has acclaimed a wide acceptance. In this particular instance, importantly both
∑ the ‘test product’ and
∑ the ‘reference product’
are usually compared in each subject, i.e., each subject serves as his/her own individual control. Obviously,
the overall incidence of inter-subject variables (or inter-volunteer variables), viz. age, weight, metabo-
lism, excretion etc., are observed to be a bare minimal.
On the basis of the glaring fact that the ‘cross-over design’ exhibits the minimal degree of inter-
subject variability, it is the most preferred method for carrying out the routine bioequivalence studies.
Essentials of Biopharmaceutics and Pharmacokinetics
260
Modus Operandi: Various steps involved are as follows:
1. First and foremost, the volunteers (subjects) are divided randomly into two groups; and subse-
quently, the ‘actual sequence’ of drug is assigned randomly.
2. When there are two altogether different ‘drug products’ (or formulations), viz. Test Formulation
(T) and Reference Formulation (R), Period I-Group I shall fi rst receive T, followed by R.
21
3. The time-gap between the actual administrations of the two selected drug products must be wide
enough so as to provide suffi cient ‘washout period’.
22
4. In actual practice, approximately 10 plasma half-lives legitimately ensures more than 99% of
elimination phenomenon, and, therefore, the considered ‘washout period’ must be at least 10
plasma half-lives.
5. Consequently, Period II shall commence soon after the completion of the respective ‘washout
period’. Besides, in the span of Period II, Group I shall duly receive R followed by T.
21
It is simply a hypothetical example, it may be the other way round, i.e., fi rst, Group I receiving R, followed by I.
22
Washout Period: It critically ensures the complete elimination of a drug before the next administration.
Let us consider a typical example when a drug substances requires a washout period of 7 days
(having a plasma half-life of approximately 10 hrs), the sequence adopted for the administration of
the two drug products may be illustrated explicitly as given in Table 4.3.
Example
Table 4.3 Suggested sequence of administration in an elaborated bioequivalence study [Period I and Period II]
Group Period I (Day 1) Period II (Day 8)
ITT
II R T
T = test formulation; R = reference for mulation.
The various steps involved in the cross-over design are as follows:
1. The observed sequence of administration (or treatment) for Group I is T–R, and for Group
II is R–T. Thus, any two drug product trial is usually known as the two-sequence trial.
2. Based on Table 4.3, one may regard a ‘2-formulation trial’ as a ‘2-period trial’. Thus, in
Period I almost 50% volunteers (subjects) of Group I do receive T, whereas, the remaining
50% volunteers [Group II] receive R. In Period II, the order is just reversed.
Explanation
Number of Volunteers Taken in a Study: In usual practice, the number of volunteers (subjects) taken
in a ‘bioequivalence study’ is solely based upon the ‘statistical parameters’. Nevertheless, 24 subjects are
the most preferred number, but a ‘bioequivalence study’ must never have less than 12 subjects.
Besides, in such an elaborated ‘bioequivalence study’, the critical blood sampling must be scheduled
Clinical Pharmacokinetics
261
Importantly, it is always advisable to schedule the blood sampling process in planned manner so as to
give an appropriate determination of these two vital estimations:
∑ C
max
and
∑ t
max
.
3.5. Statistical Methods in Bioequivalence Study
In a broader perspective, the statistical methods involved for testing bioequivalence is exclusively based
upon the following important criteria, such as:
∑ attaining 90% confi dence interval for the ratio of the means (Test/Reference) for a specifi c condi-
tion under an active investigative consideration,
∑ various pharmacokinetic parameters, viz. C
max
, AUC, are solely obtained from the statistical data, and
these need to be analyzed using ‘analysis of variance’ (ANOVA),
∑ derived data requires to be duly transformed prior to statistical analysis by making use of a ‘logarith-
mic transformation’, and
∑ provision of adequate ‘summary statistics’, e.g., median, minima and maxima.
It is, however, pertinent to state here that almost 90% confi dence interval as observed for a specifi c
parameter under active consideration must fall within an acceptable range varying between 0.8 and 1.25,
viz. 80% – 125%. In other words, the drug product (or dosage form) is regarded to be ‘bioequivalent’,
provided the actual prevailing difference between the two drug products remains <± 20%, i.e., the aver-
age rate and the degree of a bioavailability of the test formulation (T) lies very much within 20% vis-à-vis
the corresponding reference formulation(R).
3.5.1. Statistical Method Variants
The statistical methods are usually of two types, namely:
∑ Latin-square cross-over design and
∑ Balanced incomplete block design (BIBD),
which will be discussed separately in the following sections.
Latin-Square Cross-Over Design The Latin-square cross-over design relates to a standard approach
for carrying out a comparative bioavailability study by using a randomized, balanced and open-label
cross-over design. It essentially entails the following cardinal aspects:
∑ each volunteer (subject) receives each formulation just once (drug product) and
∑ each formulation is duly administered just once in each study period.
Note
Unlike the ‘parallel design’, all the volunteers do not receive the same formulation at the same
time; they are administered with different formulations during a given study period.
The fundamental components of the Latin-square cross-over design are explicitly depicted in
Table 4.4, wherein we have
Essentials of Biopharmaceutics and Pharmacokinetics
262
First Design: a 2-way cross-over design,
Second Design: a 3-way cross-over design and
Third Design: a 4-way cross-over design,
that designate one of the many possible combinations invariably encountered in such a study.
Two-Way Cross-Over Study: In this particular instance, all 12 subjects are taken to perform the
bioequivalencies of two drug products (dosage forms/formulations), viz. Treatment A and Treatment B.
Thus, we have two different segments pertaining to the study period, for instance
First Study Period: During this, 1–6 volunteers receive treatment A, while volunteers 7–12 receive
treatment B.
Second Study Period
Stage 1: It is initiated soon after the ‘washout period’ in the course of which
∑ total elimination of drug occurs and
∑ complete elimination of the drug metabolites takes place.
Stage 2: Here, the volunteers 1–6 now receive treatment B, and volunteers 7–12 receive treatment A.
Note
Thus, each volunteer (subject) serves as his own self-control.
Table 4.4 A descriptive example of Latin-square design
Two-way cross-over design
Group No. Volunteers in group Treatment for period no.
I II
1 1, 2, 3, 4, 5, 6 A B
2 7, 8, 9, 10, 11, 12 B A
Three-way cross-over design
Group No. Volunteers in group Treatment for period no.
I II III
1 1, 2, 3, 4, 5, 6 A C B
2 7, 8, 9, 10, 11, 12 B A C
3 13, 14, 15, 16, 17, 18 C B A
Four-way cross-over design
Group No. Volunteers in group Treatment for period no.
I II III IV
1 1, 2, 3, 4, 5, 6 A B C D
2 7, 8, 9, 10, 11, 12 B D A C
3 13, 14, 15, 16, 17, 18 C A D B
4 19, 20, 21, 22, 23, 24 D C B A
Clinical Pharmacokinetics
263
Advantages of Latin-Square Design: These essentially comprise:
1. It distinctly reduces the effect of inter-subject variability by means of employing each subject as
his/her own self-control.
2. It minimizes grossly the so-called carry-over effects that might come into play when a given drug
product (or dosage form) exerts its critical infl uence upon the bioavailability of a follow-up dosage
form, due to the fact that each drug product is duly preceded and succeeded by other dosage forms.
3. It predominantly lowers the time-effect upon the observed bioavailability because each drug prod-
uct (formulation) is administered during ‘each study-period’ carefully.
4. It defi nitely needs relatively a fewer number of subjects to obtain reasonably satisfactory results.
Disadvantages of Latin-Square Design: These essentially include:
1. The study usually takes a longer time because of the fact that an appropriate ‘washout period’
between the two drug-dose administrations is an absolute necessity that could be very long pro-
vided; the drug possesses a long plasma half-life (t
1/2
).
2. The total time required to complete the entire trial-study solely depends upon the exact
number of drug products (or formulations) to be evaluated in the aforesaid study. It invariably
takes a longer duration to complete the on-going study due to the increased number of drug
products being investigated.
3. Obviously, an enhanced number of study periods frequently results into a relatively higher degree
of ‘subject dropouts’, and, therefore, the entire trial-study rather becomes diffi cult.
4. Imposed ‘Medical Ethics’ doses not permit too many trial-studies to be carried out on a particular
volunteer almost at a stretch for a longer period.
Balanced Incomplete Block Design (BIBD) In true sense, BIBD helps to eliminate a substantial
amount of diffi culties usually encountered with Latin-square design.
Salient Features: The following are the predominant features:
∑ Each volunteer never receives more than two drug products.
∑ Each drug product is administered the same number of times.
∑ Each pair of drug products invariably occurs together in the same number of volunteers (subjects).
Table 4.5 records BIBD of four altogether different formulations (or dosage forms), viz., A, B, C and D.
Importantly, in this design, each volunteer (subject) specifi cally is administered with two drug products
in the following manner:
∑ each drug product is given 6 times and
∑ each pair of drug products occurs together in two volunteers (viz. dosage form pairs AB, BC, BD,
AC, AD and CD).
3.6. Bioequivalence Data: Statistical Interpretation
After having collected the data based upon an array of known statistical methods from the bioequiva-
lence studies, the same may be applied judiciously to:
∑ determine the degree of signifi cance of any noticeable difference in the ensuing rate of absorp-
tion and/or
∑ estimate the extent of absorption
Essentials of Biopharmaceutics and Pharmacokinetics
264
so as to establish appropriately the ‘bioequivalence’ specifi cally prevailing between two or more dosage
forms (formulations).
Analysis of Variance [ANOVA]: Interestingly, an analysis of variance [ANOVA] technique is largely
applicable to estimate accurately the ‘statistical differences’.
Therefore, in a critical situation when one observes a ‘statistical difference’ signifi cantly, it may become
an absolute, necessity to establish and determine whether the ‘bioequivalence data’ are signifi cant clini-
cally or not.
Table 4.5 Balanced incomplete block design (BIBD) of four different drug products
Volunteer Treatment For period no.
III
1AB
2BA
3AC
4CA
5AD
6DA
7BC
8CB
9BD
10 D B
11 C D
12 D C
Following are a few typical examples:
1. A statistically signifi cant difference of ~10% existing between two drug products is found to
be ‘insignifi cant clinically’.
2. A simple and broadly accepted rule ascertains that in a situation when the so-called ‘relative
bioavailability’ of the test formulation (T) falls very much within the range of 80%–120%
with respect to the reference standard (R), it is considered to be bioequivalent predominantly.
3. The observed difference between the ensuing bioavailabilities of the test formulations (T)
must not, in any case, be greater than ±20% of the average values of the reference standard (R).
Examples
3.7. US-FDA/EMEA Regulatory Requirements for Bioequivalence Studies
The various guidelines pertaining to the regulatory requirements for an elaborated bioequivalence study
are now easily accessible over the ‘Internet’. Various websites related to such regulatory authorities as
US–FDA: United States-Food and Drug Administration and
EMEA: European Agency for the Evaluation of Medicinal Products,
provide relevant details of the ‘Regulatory Requirements’.
Clinical Pharmacokinetics
265
Table 4.6 records the vivid comparison of the various aspects of the regulatory requirements of US-FDA
and EMEA.
Remarks: The overall ‘Regulatory Requirements’ as stipulated under the US-FDA appears to be more
stringent and safer.
3.8. Good Clinical Practices (GCPs) in Bioequivalence
Good clinical practices [GCPs] designate articulately an international, ethical and mandatory quality
standard pertaining to various ‘Clinical Trails’ with respect to
∑ designing,
∑ conducting,
∑ recording and
∑ reporting,
which essentially involve the ‘active participation’ of the healthy human volunteers (or subjects). Efforts
should be geared to adopt only the ‘Appropriate Guidelines’, e.g., ICH, GCP, while generating mean-
ingful, reliable and authentic data for the required submission to the respective ‘Regulatory Authorities’.
Modus Operandi: In usual practice, the relevant and appropriate ‘GCP-Guidelines’ must be properly
drawn out for carrying out each and every phase of the study. Furthermore, the ‘Standard Operating
Procedures [SOPs]’ must be outlined explicitly. Ultimately, the ‘specifi c documents’ related to data col-
lection must be so designed to maintain a very high standard of GCP.
Table 4.6 US-FDA and EMEA: comparison of the regulatory requirements
S. No. Characteristic features EMEA US-FDA
1 Conditionalities to prove
‘bioequivalence’.
C
max
; AU C
0 − i
; AU C
∞
; C
max
; AU C
0 − t
; AU C
∞
;
2 Confi dence interval for C
max
. Yes. Ranges between 80% and
125% (but if larger it can be
justifi ed easily).
Yes. Ranges between 80% and
125%.
3 Need for ‘steady-state’. Yes. If the drug product is of
sustained-release type.
Not required.
4 Need for a food-related effect
study.
For immediate release, it is
required whether there exists a
reported food effect associated
with ‘innovator product’. It is
applicable to the sustained-
release dosage forms.
Yes. Applicable only if the effect
of food is clearly specifi ed/
pronounced on the labelling
itself explicitly.
5 Need for reasonable, ‘metabolic
data profi le’.
Yes. Provided the ‘drug’ is a
‘prodrug’ or if the metabolite
contributes appreciably to the
effi cacy for the ‘drug product.’
Supportive evidence required.
6 AUC percentage needs to be
observed precisely, viz. Ratio
of
0-t 0-
AUC /AUC .
∞
More than 80%. More than 80%.
Essentials of Biopharmaceutics and Pharmacokinetics
266
Formulation of Clinical SOPs: In a broader perspective, the clinical SOPs must be so designed that
it must entirely cover the following laid down aspects critically related to the ‘bioequivalence study’ right
from the initial step to the fi nal step (i.e., storage of samples properly), namely:
∑ Study protocol,
∑ Approval of ethical committee,
∑ Proper selection of ‘trained staff ’ and available facilities,
∑ Recruitment of volunteers (or subjects),
∑ Retrieving trial samples,
∑ Carrying out actual ‘bioequivalence study’ (i.e., collection and recording of data) and
∑ Handling and proper storage of samples.
Highlights of SOPs: The following are highlights:
∑ SOPs must fully establish the ‘clinical aspect of the bioequivalence study’,
∑ SOPs should aid in carrying out most of the routine tasks and
∑ SOPs must ascertain that a ‘standard stipulated procedure’ be followed throughout the ‘bioequiva-
lence study’.
Information Included in SOPs: These include:
∑ Name of SOP, SOP-number and Effective date;
∑ Main aims and objectives of the SOP;
∑ Detailed stepwise instructions to perform the procedure;
∑ Entire list of materials/equipments required for the procedure and
∑ Endorsement (with signatures) of authorized person(s) including principal investigator.
Systematic Collection of SOP-Data: The SOP-data duly collected from a specifi c study method
need to be arranged systematically. It ensures not only accuracy and consistency, but also provides integ-
rity. There are several ‘data-collection documents’ which are put into practice commonly, e.g., Printed
Forms, Logbooks, Case Reports, Clinical Reports etc., and these documents must be adequately main-
tained and archived.
23
Haematocrit Value: It refers to the percentage of erythrocytes in a specifi c volume of whole blood.
Note
It is absolutely necessary that a ‘Comprehensive Blood Analysis’ must be carried out in the course
of complete screening of all volunteers (subjects) and such data must be duly stored in the ‘Subject
Bank’ before the commencement of a ‘bioequivalence study’ and after completion of the study.
Parameters of Blood Analysis: These essentially include
1. WBC count
2. Haematocrit value
23
3. Haemoglobin %
4. Sedimentation
5. Blood sugar
Clinical Pharmacokinetics
267
6. Serum creatinine
7. Serum Na
+
concentration level
8. Serum K
+
concentration level
9. Serum Ca
2+
concentration level
10. Serum bilirubin level
11. SGOT [Serum Glutamate Oxaloacetate Amino transferase]
12. SGPT [Serum Glutamate Pyruvate Amino transferase]
13. Total cholesterol
14. Total protein
15. Alkaline phosphatase
Note
In addition, all the volunteers (subjects) must be thoroughly screened for HIV, hepatitis and
syphilis infections and recorded duly in the ‘Subject Bank’.
3.8.1. Commonly Observed Non-Compliances in Bioequivalence Study
Following are some of the observed non-compliances in a bioequivalence study, and, therefore, essen-
tially need a special attention, such as:
∑ Subjects (volunteers) not receiving the drug products (dosage forms) either as the Test Sample (T) or
the Reference Sample (R) strictly according to the randomized drug schedule.
∑ Collected ‘biological samples’ compromised heavily under undue identifi cation, and improper han-
dling or storage.
∑ Ill-maintained ‘drug accountability records’.
∑ Inadequate reporting of ‘adverse drug reactions’, viz. diarrhoea, excessive vomiting, that are largely
recognized to affect both absorption and elimination of drug substances signifi cantly.
∑ Grossly inadequate medical supervision and proper coverage of all subjects.
∑ Protocol deviations, if any, not reported to the sponsor.
∑ Complete ignorance/failure to adhere strictly towards the respective inclusion or exclusion criteria.
∑ Consent (S) of subject not recorded properly.
∑ Other miscellaneous aspects related to the improper/inadequately health and welfare management
of the subjects that are ignored for one reason or the other.
Overall Remarks: In short, it may be concluded that the respective ‘bioequivalence studies’ do occupy a
‘coveted status’ in the ever-expanding spheres of the scientifi c studies. It essentially implies and assures the
entire health-care professionals across the globe that two drug products (or dosage forms) of the same drug
molecule (may be produced by different manufacturers) shall undoubtedly possess the similar degree of
∑ effi caciousness,
∑ toxicity profi le and
∑ adverse effects.
3.9. Exemptions in Bioequivalence Study
Certain exemptions are effectively implemented in ‘bioequivalence study’, which essential comprise
Essentials of Biopharmaceutics and Pharmacokinetics
268
1. The ‘drug product’ differs exclusively in the strength (or dose level), however, in such a situation
the following laid down conditionalities must be satisfi ed and adhered to:
∑ Drug pharmacokinetic profi le must be ‘linear’.
∑ Both in lower and higher strength drug products, the prevailing ‘ratio’ between the active sub-
stance (drug) and the excipients must remain the same.
∑ Premises of manufacturing the drug product for both lower and higher strengths should be
the same.
∑ Two ‘drug products’ under study should have the same (or ~ same) ‘dissolution rate’.
2. If minor necessary alterations have been duly carried out in the drug product (or formulation) or
method of manufacturing process, and based on the supportive fact that these affected alterations may
be proved convincingly as quite reasonably irrelevant for the bioavailability of the drug substance.
3. The drug product (or formulation) needs to be administered parenterally in the form of a solution.
Besides, such dosage forms must be available commercially.
4. The dosage form (or drug product) may be an oral liquid available in the form of a solution, viz.
oral suspensions elixirs, syrups etc.
3.10. Bioequivalence Studies: Not Necessary
There are quite a few glaring situations wherein the bioequivalence studies are not necessary at all. The
typical instances are as follows:
∑ Drug product happens to be in a gaseous state meant for inhalation, e.g., chloroform, nitrous oxide etc.
∑ Drug products are meant for ‘local application’ which are intended to exhibit the desired therapeutic
effect without any systemic absorption whatsoever.
3.11. Absolute Bioavailable Dosage
Bioequivalency may be explained when two drug products prevalently differ in bioavailability with regard to
∑ rate of absorption of the drug or
∑ quantum of drug absorbed.
It is, therefore, pertinent to state here that in a situation when two drug products are to be considered as
bioequivalent, they should never, under any circumstances, exhibit variance signifi cantly in their
∑ bioavailable dose or
∑ rate of supply.
Based on the above facts, one may duly explain the ‘absolute bioavailable dose’ as the ‘dose which a
patient absorbs actually, in contrast to the dose that the patient takes’.
In reality, the ‘bioavailable dose’ could be calculated easily from the value of ‘f ’ ( i.e., the fraction of the
administered dose) by rearranging the following expression:
Bioavailable dose
Administereddose
f =
(aj)
From Equation (aj) we may derive (by rearranging):
Bioavailable dose = ×administrated dosef
(ak)